Quantitative Analytic Studies In Epilepsy

Author : Shatrunjai P. Singh
Publisher :
ISBN 13 :
Total Pages : 126 pages
Book Rating : 4.:/5 (954 download)

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Download or read book Quantitative Analysis on the Origins of Morphologically Abnormal Cells in Temporal Lobe Epilepsy written by Shatrunjai P. Singh and published by . This book was released on 2015 with total page 126 pages. Available in PDF, EPUB and Kindle. Book excerpt: Epilepsy is a common and devastating neurological disease with no real preventive or cure. In most cases of acquired epilepsy, an initial precipitating injury to the brain is followed by a silent period which eventually culminates into the development of spontaneous, recurrent seizures. This interval between the primary insult and the first seizure is referred to as the latent period of epileptogenesis and is characterized by abnormal morphological and physiological changes in the hippocampus. In the studies described herein, I aim to elucidate changes in the different phases of epileptogenesis with the end goal of deciphering critical epileptogenic mechanisms. To study the initial stages of epileptogenesis, I employed the early kindling model. In this protocol, it is possible to administer a limited number of stimulations sufficient to produce a lifelong enhanced sensitivity to stimulus evoked seizures without associated spontaneous seizures. In these experiments, I characterized the morphology of GFP-expressing granule cells from Thy-1 GFP mice either one day or one month after the last evoked seizure. I observed several morphological changes at the one day time point, which all normalized to control levels at the one month time point. Interestingly, I did not observe the presence of basal dendrites, frequently observed in other models of epilepsy. These findings demonstrate that the early stages of kindling epileptogenesis produces transient morphological changes but not the dramatic pathological rearrangements of dentate granule cell structure seen in typical models associated with spontaneous seizures. To study epileptogenesis after the incidence of spontaneous, recurrent seizures, I used the pilocarpine model of epilepsy. Our lab has previously used this model to show that adult hippocampal neurogenesis is profoundly altered under epileptic conditions, leading to the production of morphologically abnormal dentate granule cells. Under epileptic conditions, these adult generated cells migrate to ectopic locations and develop misoriented basal dendrites. Although it has been established that these abnormal cells are newly-generated, it is not known whether they arise ubiquitously throughout the progenitor cell pool or are derived from a smaller number of bad actor progenitors. To explore this question, I describe clonal analysis experiments conducted in epileptic mice expressing the brainbow fluorescent protein reporter construct in dentate granule cell progenitors. Brain sections were rendered translucent so that entire hippocampi could be reconstructed and all fluorescently-labeled cells identified. The findings revealed that a small number of progenitors produced the majority of ectopic cells in epileptic mice, indicating that either the affected progenitors or their local micro-environments had become pathological. By contrast, granule cells with basal dendrites were equally distributed among clonal groups. These findings strongly predict that distinct mechanisms regulate different aspects of granule cell pathology in epilepsy. The experiments described here utilize different models of epilepsy and employ cutting edge technology to provide valuable insight into the process of epileptogenesis. The results and ideas presented here are intended to advance our knowledge of epilepsy and eventually lead to better antiepileptic therapies.